Diltiazem, a typical calcium antagonist, has been used throughout the world as a remedy for angina and hypertension. Among the four possible stereoisomers of diltiazem, only the (+)-(2S,3S)-isomer exhibits potent coronary vasodilating activity. Therefore, diltiazem has been developed and marketed as a single isomer. For the synthesis of diltiazem, many processes have been extensively investigated and at present it is mainly manufactured by the route using the optically active (−)-trans methyl glycidate as a key intermediate, which is prepared via enzymatic methods. However, there is an inherent drawback to the optical resolution in that the maximum yield of one enantiomer cannot exceed 50%. Although several approaches for the asymmetric synthesis of diltiazem have been reported, for reasons involving enantiomeric purity and overall efficiency, a more efficient method is needed.
Reference is made to U.S. Pat. No. 5,869,697, (1999) wherein synthesis of diltiazem was carried out by using optically pure chiral diols. The inherent disadvantage is the optically pure diols used are expensive involving tedious experimental procedures. Reference is also made to U.S. Pat. No. 6,180,785 (2001) wherein synthesis of diltiazem was carried out by using optically pure chiral diols. The inherent disadvantage is the optically pure diols used are expensive, involving tedious experimental procedures.
Reference is made to J. Org. Chem. 1992, 57, 851 wherein optically active trans-phenylglycidic acid ester is prepared using chiral auxiliary followed by a stereoselective opening of the epoxide by various substituted aminothiophenols to give the desired intermediate ester for diltiazem. The inherent disadvantage is the use of stoichiometric amount of chiral auxiliary. Reference is also made to Tetrahedron Lett. 2001, 42, 1313 wherein optically active trans-phenylglycidic acid ester is prepared via chiral oxazaborolidine-mediated Mukaiyama aldol reaction followed by reduction and cyclization. The inherent disadvantage is the use of a stoichiometric amount of an expensive reagent.
Reference is made to J. Org. Chem., 1996, 61, 6730 wherein optically active diols were prepared via enantioselective lipase catalyzed hydrolysis of threo-diacetate ethyl ester which leads to (+)-diltiazem precursors (2S,3R)-diol and (2R,3S)-diol. The inherent disadvantage is the recovery of an entirely toxic osmium tetroxide to prepare threo-diol ester.